Mitochondrial metabolic dysfunction and non-alcoholic fatty liver disease: new insights from pathogenic mechanisms to clinically targeted therapy

Metabolic dysfunction-associated fatty liver disease (MAFLD) is among the most widespread metabolic disease globally, and its associated complications including insulin resistance and diabetes have become threatening conditions for human health. Previous studies on non-alcoholic fatty liver disease (NAFLD) were focused on the liver's lipid metabolism. However, growing evidence suggests that mitochondrial metabolism is involved in the pathogenesis of NAFLD to varying degrees in several ways, for instance in cellular division, oxidative stress, autophagy, and mitochondrial quality control. Ultimately, liver function gradually declines as a result of mitochondrial dysfunction. The liver is unable to transfer the excess lipid droplets outside the liver. Therefore, how to regulate hepatic mitochondrial function to treat NAFLD has become the focus of current research. This review provides details about the intrinsic link of NAFLD with mitochondrial metabolism and the mechanisms by which mitochondrial dysfunctions contribute to NAFLD progression. Given the crucial role of mitochondrial metabolism in NAFLD progression, the application potential of multiple mitochondrial function improvement modalities (including physical exercise, diabetic medications, small molecule agonists targeting Sirt3, and mitochondria-specific antioxidants) in the treatment of NAFLD was evaluated hoping to provide new insights into NAFLD treatment.